[unreadable] [unreadable] This is a competitive renewal application for years 16-20 of Program Project Grant HL-44612, which provides support for a coordinated, multi-disciplinary investigation of molecular and cellular mechanisms important to the field of transfusion medicine - a discipline that, despite its obvious importance to the nation's health, has historically been [unreadable] underrepresented in both training and research resources. Our application reflects ongoing, close collaborative ties that have existed amongst the Project Leaders for more than a decade, and who remain committed to interrelated research projects centered around the biology of blood and vascular cells. In PROJECT 1, Peter and Debra Newman propose four interrelated aims that seek to further our understanding of the cell surface receptors and associated signaling pathways that regulate platelet activation and adhesion. In PROJECT 2, Dick Aster proposes to continue his investigation of pre-existing, "naturally-occurring" antibodies that cause acute platelet destruction in patients exposed to abciximab or ligand-mimetic GPIIb/IIIa inhibitors, and may have important implications for other immune disorders. PROJECT 3, led by Cheryl Hillery, seeks to define how blood coagulation pathways contribute to sickle cell-induced organ damage, and to explore potential therapies that limit both acute episodes of vaso-occlusion and the accompanying chronic organ damage. PROJECT 4, led by Bob Montgomery continues to explore the structural requirements for VWF biosynthesis that lay the foundation for an entirely novel replacement therapy approach for the treatment of patients with severe hemophilia A. In PROJECT 5, Hartmut Weiler proposes a series of investigations designed to explore the mechanisms by which mice and humans who carry the Leiden mutation of blood coagulation factor V (fVLeiden) are protected against the catastrophic complications of sepsis. The Administrative Core will oversee and coordinate the day-to-day scientific and fiscal operation of the Program. The Shared Instrumentation Core will continue to provide centralized instrumentation and expertise for DNA sequence analysis, peptide synthesis, microscopy/digital image analysis, histology, flow cytometry and cell sorting, BIAcore analysis, and monoclonal antibody production. The Transgenic/Knockout Mouse Core will assist with vector design, transgenic mouse production, embryonic stem cell growth and transfection, breeding, and animal husbandry. Taken together, the overall scientific synergy of ideas, reagents and expertise afforded by these multiple collaborations should enable this Program Project in Transfusion Medicine Research to advance our understanding of the biology of blood and vascular cells, and to apply findings made toward treating blood diseases and enhancing the effectiveness of transfusion therapy. [unreadable] [unreadable]